LETTER TO THE EDITOR

Wegener’s granulomatosis with dengue fever: an unusualassociation

Dear Editor,

A 14-year-old unmarried girl was admitted to our hos-

pital with a history of high-grade continuous fever for

15 days, along with mild non-productive cough for

7 days and conjunctival congestion for 4 days. On fur-

ther interrogation, she revealed that she experienced

an episode of epistaxis 3 days prior to onset of fever

along with a blood-stained purulent discharge from

her right ear which persisted for 2 days. She again had

an episode of epistaxis on the day following her

admission. On examination, she was found to have

fever (38.9�C) and tachycardia (110 beats/min). Sys-

temic examination revealed hemorrhagic spots on

right nasal mucosa and tenderness over the right

tragus. All other examination findings were normal.

Possibilities of viral hemorrhagic fever, sepsis, hema-

tological malignancy or aplastic anemia were kept

under consideration and investigations followed. A

broad-spectrum antibiotic in the form of cefoperaz-

one + sulbactum (1 g + 500 mg) twice daily was also

initiated empirically. The complete hemogram

revealed Hemoglobin 8.7 g/dL, total leukocyte count

12 100/mm3, neutrophil72, lymphocyte22, platelet

count 480 000/mm3). The erythrocyte sedimentation

rate was 62 mm/1st hour. Liver function tests, blood

sugar and serum urea and creatinine values were nor-

mal. Tests for human immunodeficiency virus anti-

bodies were found to be non-reactive. Blood culture

was found to be negative. Enzyme-linked immunosor-

bent assay done for detection of Dengue antibodies

was found to be positive! There was presence of both

immunoglobulin (Ig)M and IgG types of Dengue anti-

bodies in the serum of the patient. A raised platelet

count in the background of a seropositivity for Den-

gue infection was considered an unusual finding. So it

was followed up with some more investigations.

Urine analysis revealed strong presence of occult

blood with 60–80 red blood cells per high power field

(RBC/hpf). The albumin/creatinine ratio was 10 mcg/

mg. The urine culture was negative. At this juncture, a

chest X-ray done incidentally as a part of routine

investigation revealed two thick-walled cavity lesions

located in both the right and left lung fields. We fol-

lowed this up with sputum examination for acid fast

bacilli and Gram-staining bacteria. Both microscopy

and culture were found to be negative. So we decided

to undertake a contrast-enhanced computed tomogra-

phy (CT) scan of the thorax. This revealed multiple

thick-walled lesions in both lung fields and few nodu-

lar lesions (Fig. 1). As per the radiologist’s opinion,

this was suggestive of Wegener’s granulomatosis.

CT-guided fine-needle aspiratory cytology from the

lesion confirmed the presence of granulomatous

inflammation. Test for detection of antineutrophil

cytoplasmic antibody was positive with presence of

antiproteinase 3 antibody at a level of 70.27 U/mL

(normal < 6 U/mL).

With these results, a diagnosis of Wegener’s granulo-

matosis was established for this patient. The patient

was hence put on intravenous methylprednisolone

Figure 1 Contrast-enhanced computed tomography scan(thorax) showing multiple bilateral thick walled lesions andnodular lesions.

International Journal of Rheumatic Diseases 2011

ª 2011 The AuthorsInternational Journal of Rheumatic Diseasesª 2011 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd

500 mg for 3 days, followed by 40 mg of daily oral

prednisolone. Oral cyclophosphamide was started at a

dose of 75 mg/day. An ear nose and throat specialist’s

opinion was taken, who observed the presence of

active chronic suppurative otitis media in the right ear

with presence of a swelling in the external auditory

canal with supratip depression. In the left ear, there

was presence of central perforation with adhesion and

atelectasis. Hemorrhagic spots were described in the

right nasal mucosa. The ophthalmologist opined that

the congestion in her eyes were due to limbic kerato-

conjunctivitis. However, a kidney biopsy done to eval-

uate the hematuria revealed non-specific changes.

However, it should be mentioned here that the kidney

biopsy was done following the initiation of immuno-

suppressive therapy because of the emergent nature of

the condition.

After 2 weeks of immunosuppressive therapy, urin-

analysis revealed only 2–3 RBC/hpf and after 6 weeks

of therapy, there were no detectable RBCs in the urine

sample. Follow-up chest X-ray done after 6 weeks

showed reduction in size of the right-sided lesion and

complete disappearance of the left-sided lesion. The

patient is now on regular follow-up and is doing well

except for the development of a saddle nose deformity.

Wegener’s granulomatosis is a multisystem small

vessel necrotizing vasculitis characterized by formation

of granulomatous lesions. It is more common in the

fourth and fifth decades and in Caucasian patients. It

is also rare in populations younger than 19 years,

which comprises only 0.1–15% of cases.1 The cause of

Wegener’s granulomatosis is unknown. Several

attempts to link infectious agents to this disease have

been unconvincing. However, studies have shown

higher prevalence of antibodies against Epstein–Barr

virus and cytomegalovirus in patients with Wegener’s

granulomatosis.2,3 Respiratory syncytial virus infection

has also been described in association with this condi-

tion.4 It is possible that these viral infections may have

a putative role in initiation and exacerbation of the

disease.

In our case, we found the presence of a Dengue

infection at the onset of the disease. Dengue fever is a

flaviviral infection which is very commonly detected

in India. In Dengue pathology, a number of cytokines

and chemokines like tumor necrosis factor alpha

(TNF-a), interleukin (IL)-6, IL-8 and RANTES (regu-

lated upon activation, normal T cell expressed and

secreted) have been detected in the sera of patients

and in endothelial cell culture supernatants in some

studies.5–7 It has been found to activate the comple-

ment system and immune cells.6 Antibodies produced

during Dengue infection has been found to cross-react

with human platelets and endothelial cells.8 The anti-

NS-1 antibodies produced have been found to be at

least partially responsible for reactivity with endothelial

cells.5 Anti-NS-1 antibody has been demonstrated to

have stimulated cytokine and chemokines production.5

However, to the best of our knowledge, no study till

now has shown any association between Dengue infec-

tion and Wegener’s granulomatosis. It can be viewed as

a novel finding because as seen in our case, it may be

hypothesized that such an infection could have precipi-

tated the disease in an otherwise rare category of the

population. There was also concurrent presence of

active chronic suppurative otitis media in this patient.

However, in the medical literature we could not find

the mention of chronic suppurative otitis media as a

triggering factor for any systemic vasculitic disease.

Moreover, the patient also had a history of intermittent

discharge from her ears for many years. So, it seems less

likely to us that it could also have acted as a triggering

factor. Viral infections on the other hand are known

potential triggering factors for autoimmune diseases. It

is possible that the Dengue infection created an anti-

genic stimulus needed to activate a dormant Wegener’s

granulomatosis. Alternatively Dengue might have trig-

gered a secondary vasculitis. Direct cytopathic effect on

endothelial cells, molecular mimicry, increased cytokine

production and complement activation may contribute

to the development of vasculitis.9,10 Nevertheless, we

must admit the possibility that the Dengue infection

and Wegener’s granulomatosis were concurrently-occur-

ring causally unrelated events, which cannot be ruled

out altogether.

Anirban GHOSH,1 Arnab BANERJEE,1 Sandip SAHA,1

Arindam PANDE1 and Biswadip GHOSH2

1Department of General Medicine, Medical College and

Hospital, Kolkata, India; and 2Department of

Rheumatology, IPGME&R, Kolkata, India

Correspondence: A. Ghosh,

email: ani.medico@gmail.com

REFERENCES

1 Calabrese LH, Molloy ES, Duna G (2008) Antineutrophil

cytoplasmic antibody-associated vasculitis. In: Firestein

GS, Budd RC, Harris ED Jr, McInnes IB, Ruddy S, Sergent

JS (eds) Kelley’s Textbook of Rheumatology, 8th edn, pp

1429–51. W.B. Saunders, Philadelphia.

Letter to the Editor

2 International Journal of Rheumatic Diseases 2011

2 Lidar M, Lipschitz N, Langevitz P, et al. (2009) Infectious se-

rologies and autoantibodies in Wegener’s granulomatosis

and other vasculitides: novel associations disclosed using

the Rad BioPlex 2200. Ann NY Acad Sci 1173, 649–57.

3 Varani S, Mastroianni A, Frascaroli G, et al. (2009) Gen-

eralized Wegener’s granulomatosis in an immunocompe-

tent adult after cytomegalovirus mononucleosis and

bacterial urinary tract infection. Arthritis Rheum 60,

1558–62.

4 Multz AS, Keil K, Karpel JP (1992) Respiratory syncytial

virus infection in an adult with Wegener’s granulomato-

sis. Chest 101(6), 1717–8.

5 Lin CF, Lei HY, Liu CC, et al. (2004) Autoimmunity in

dengue virus infection. Dengue Bull 28, ch-07.

6 Rothman AL, Ennis FA (1999) Immunopathogenesis of

dengue hemorrhagic fever. Virology 257, 1–6.

7 Avirutnan P, Malasit P, Seliger B, Bhakdi S, Husmann M

(1998) Dengue virus infection of human endothelial cells

leads to chemokine production, complement activation,

and apoptosis. J Immunol 161, 6338–46.

8 Lin CF, Lei HY, Shiau AL, et al. (2003) Antibodies from

dengue patient sera cross-react with endothelial cells and

induce damage. J Med Virol 69, 82–90.

9 Rodriguez-Pla A, Stone JH (2006) Vasculitis and systemic

infections. Curr Opin Rheumatol 18, 39–47.

10 Pagnoux C, Cohen P, Guillevin L (2006) Vasculitides sec-

ondary to infections. Clin Exp Rheumatol 24 (Suppl 41),

S71–81.

Letter to the Editor

International Journal of Rheumatic Diseases 2011 3